The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Antibiotic Therapy for 6 or 12 Weeks

for Prosthetic Joint Infection
L. Bernard, C. Arvieux, B. Brunschweiler, S. Touchais, S. Ansart, J.-P. Bru, E. Oziol,
C. Boeri, G. Gras, J. Druon, P. Rosset, E. Senneville, H. Bentayeb, D. Bouhour,
G. Le Moal, J. Michon, H. Aumaître, E. Forestier, J.-M. Laffosse, T. Begué,
C. Chirouze, F.-A. Dauchy, E. Devaud, B. Martha, D. Burgot, D. Boutoille,
E. Stindel, A. Dinh, P. Bemer, B. Giraudeau, B. Issartel, and A. Caille​​

A BS T R AC T

BACKGROUND
The management of prosthetic joint infection usually consists of a combination of The authors’ full names, academic de-
surgery and antimicrobial therapy. The appropriate duration of antimicrobial grees, and affiliations are listed in the
Appendix. Address reprint requests to Dr.
therapy for this indication remains unclear. Bernard at the Division of Infectious Dis-
METHODS eases, University Hospital Bretonneau,
2 Boulevard Tonnellé, 37044 Tours CEDEX 9,
We performed an open-label, randomized, controlled, noninferiority trial to com- France, or at ­l​.­bernard@​­chu-tours​.­fr.
pare 6 weeks with 12 weeks of antibiotic therapy in patients with microbiologically
N Engl J Med 2021;384:1991-2001.
confirmed prosthetic joint infection that had been managed with an appropriate DOI: 10.1056/NEJMoa2020198
surgical procedure. The primary outcome was persistent infection (defined as the Copyright © 2021 Massachusetts Medical Society.

persistence or recurrence of infection with the initial causative bacteria, with an

antibiotic susceptibility pattern that was phenotypically indistinguishable from that
at enrollment) within 2 years after the completion of antibiotic therapy. Nonin-
feriority of 6 weeks of therapy to 12 weeks of therapy would be shown if the upper
boundary of the 95% confidence interval for the absolute between-group difference
(the value in the 6-week group minus the value in the 12-week group) in the percent-
age of patients with persistent infection within 2 years was not greater than 10 per-
centage points.
RESULTS
A total of 410 patients from 28 French centers were randomly assigned to receive
antibiotic therapy for 6 weeks (205 patients) or for 12 weeks (205 patients). Six
patients who withdrew consent were not included in the analysis. In the main
analysis, 20 patients who died during follow-up were excluded, and missing out-
comes for 6 patients who were lost to follow-up were considered to be persistent
infection. Persistent infection occurred in 35 of 193 patients (18.1%) in the 6-week
group and in 18 of 191 patients (9.4%) in the 12-week group (risk difference, 8.7
percentage points; 95% confidence interval, 1.8 to 15.6); thus, noninferiority was
not shown. Noninferiority was also not shown in the per-protocol and sensitivity
analyses. We found no evidence of between-group differences in the percentage of
patients with treatment failure due to a new infection, probable treatment failure,
or serious adverse events.
CONCLUSIONS
Among patients with microbiologically confirmed prosthetic joint infections that
were managed with standard surgical procedures, antibiotic therapy for 6 weeks
was not shown to be noninferior to antibiotic therapy for 12 weeks and resulted
in a higher percentage of patients with unfavorable outcomes. (Funded by Pro-
gramme Hospitalier de Recherche Clinique, French Ministry of Health; DATIPO
ClinicalTrials.gov number, NCT01816009.)
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 The n e w e ng l a n d j o u r na l
P
rosthetic joint infections are asso-
ciated with considerable morbidity. The
treatment of this condition is challenging
and costly.1 The management of prosthetic joint
infection involves both surgery and antimicro-
bial therapy. The classic surgical options include
one-stage or two-stage implant exchange, resec-
tion arthroplasty (with or without arthrodesis),
or débridement with implant retention. Treat-
ment failure occurs in 11 to 35% of patients.1,2
The duration of antibiotic therapy in patients
with prosthetic joint infection is primarily based
on expert recommendations rather than evi-
dence.3,4 Patients usually receive long courses of
antibiotic therapy, which can be up to 6 months
for staphylococcal infections.1,5 However, several
studies suggest that shorter courses may be ap-
propriate for most cases of prosthetic joint infec-
tion or osteomyelitis2,6-8 and may be associated
with reductions in the duration of hospital stay,
incidence of adverse events, and emergence of mi-
crobiologic resistance.8 We conducted the Dura-
tion of Antibiotic Treatment in Prosthetic Joint
Infection (DATIPO) trial to compare the efficacy
and safety of a short course of antibiotic treat-
ment (6 weeks) with those of a longer course (12
weeks) in patients with prosthetic joint infections
that had been caused by various pathogens and
managed with appropriate surgical procedures.
Me thods
Trial Design and Oversight
The DATIPO trial was an investigator-initiated,
multicenter, open-label, parallel-group, random-
ized, controlled, noninferiority trial. The trial
protocol, available with the full text of this article
at NEJM.org, was approved by the appropriate
French ethics committee (Comité de Protection
des Personnes de Tours). All the patients provided
written informed consent. The authors vouch for
the accuracy and completeness of the data and
for the fidelity of the trial to the protocol.
Patients
Patients were eligible to participate in the trial if
they were 18 years of age or older and had pros-
thetic joint infection (hip or knee) that had been
managed with an appropriate surgical procedure
(either one-stage or two-stage implant exchange
or débridement with implant retention). Pros-
thetic joint infection was identified by the pres-
ence of at least one clinical symptom (pain, fever,
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of m e dic i n e
fistula, outflow around the scar, erythema, or
swelling) and a microbiologically documented
infection.
The criterion for microbiologic identification
of the causative agent from surgical samples was
a minimum of two bacterial cultures of different
samples obtained during the same surgical pro-
cedure that yielded the same pathogen. If the
pathogen was any skin bacteria (e.g., coagulase-
negative staphylococcus or Cutibacterium acnes,
corynebacterium, lactobacillus, or micrococcus),
at least three cultures yielding the same patho-
gen were required for identification. We exclud-
ed patients who were receiving an effective anti-
biotic therapy that had been initiated more than
21 days before screening; had undergone more
than one prosthesis replacement strategy for
sepsis at the affected joint; had prosthetic joint
infection that was caused by mycobacterium,
actinomyces, a fungal pathogen, or brucella; had
a life expectancy of less than 2 years; or were
currently included in another randomized trial.
Additional details of the eligibility criteria are
provided in the Supplementary Appendix, avail-
able at NEJM.org, and the protocol.
Randomization and Interventions
An independent statistician prepared a computer-
generated 1:1 randomization list using permuta-
tion blocks of variable sizes, stratified according
to the initial surgical procedure (one-stage or
two-stage implant exchange or débridement with
implant retention), infected joint (hip vs. knee),
and episode of infection (first vs. at least the
second). Day 0 (baseline) was the first day of
effective antibiotic treatment, defined as the
administration of active antibiotics for the type
or types of bacteria causing the infection, as
determined with the use of phenotypic methods
for antimicrobial susceptibility testing. The days
that empirical antibiotic therapy was adminis-
tered before the results of susceptibility testing
were available were counted if the antibiotic ther-
apy was determined retrospectively to be active.
Randomization was performed by trained
staff members with the use of a secure, central-
ized, interactive, Web-based response system
within the first 21 days after day 0. The patients
were randomly assigned to receive 6 weeks or 12
weeks of antibiotic therapy as soon as possible
after the surgical procedure. The patients and
the clinicians who administered the interven-
tions were aware of the trial-group assignments;
nejm.org May 27, 2021
 Antibiotic Ther apy for Prosthetic Joint Infection

however, primary outcome events were validated ries of treatment failure are provided in the Sup-
by an adjudication committee of three indepen- plementary Appendix. All confirmed or suspected
dent specialists (one infectious diseases special- failure events that were identified during follow-
ist, one orthopedic surgeon, and one bacteri- up were subsequently verified by the indepen-
ologist) who were unaware of the trial-group dent adjudication committee. The members of
assignments. The electronic case-record form the committee determined the category of each
was included in the secure, interactive, Web- suspected treatment failure by consensus. The
based response system that was available at each outcomes of patients with confirmed or sus-
trial center, as provided and managed by the pected failure were reviewed separately by the
staff of the Methodology, Biostatistics, and Data three members of the adjudication committee.
Management Unit of Tours University Hospital, In case of disagreement, consensus among the
who were not involved in patient recruitment. committee members was obtained during a tele-
The empirical treatment that was adminis- phone meeting. The committee reviewed data
tered before the results of susceptibility testing for 112 patients. Immediate agreement among
were available, as well as the definitive treat- the three committee members was reached for
ment, was chosen by the treating physician ac- 67 patients, and consensus was needed for 45.
cording to guidelines of Société de Pathologie The primary outcome was persistent infection
Infectieuse de Langue Française9 or the Infec- within 2 years after the end of antibiotic therapy.
tious Diseases Society of America,5 without Secondary outcomes were new infection, proba-
knowledge of whether the duration of antibiotic ble treatment failure, hospital length of stay
treatment was 6 weeks or 12 weeks. No mainte- (from day 0), functional outcome, and safety
nance or suppressive antibiotic therapy was ad- outcomes. The functional outcome was estab-
ministered after the scheduled end of treatment. lished with the use of the Merle d’Aubigné and
The choice of surgical procedure was guided by Postel score for the hip10 and the Knee Society
recommendations made by Société Française de score11 (see the Supplementary Appendix). Safety
Chirurgie Orthopédique et Traumatologique or outcomes included serious adverse events and
the American Academy of Orthopaedic Surgeons. laboratory values during treatment and follow-up.
Additional information on the methods of the
trial is provided in the Supplementary Appendix. Statistical Analysis
Assuming that persistent infection would occur
Assessments and Outcomes in 15% of the patients in both trial groups, we
Results of clinical assessments and patient-­ estimated that a sample size of 410 patients (205
reported outcome measures were recorded at en- patients per group) would give the trial 80%
rollment and at 6, 12, 24, and 52 weeks after day power to show noninferiority of 6 weeks of anti-
0 and at 104 weeks after the planned completion biotic therapy to 12 weeks of therapy, with a
date of antibiotic therapy. Telephone follow-up noninferiority margin of 10 percentage points,
took place at 9, 36, and 76 weeks after day 0. at a one-sided alpha level of 0.025. The main
All events of treatment failure that occurred analysis of the primary outcome was performed
within 2 years after the end of antibiotic therapy in the modified intention-to-treat population that
were recorded. There were three categories of included all the patients who had undergone
treatment failure: persistent infection, defined randomization, except those who withdrew con-
as the persistence or recurrence of infection with sent for participation or who died; missing out-
the initial causative bacteria, with an antibiotic comes for the patients who were lost to follow-
susceptibility pattern that was phenotypically up were considered to be persistent infections,
indistinguishable from that at enrollment; new as planned in the protocol. We determined that
infection, defined as treatment failure with a noninferiority of 6 weeks of therapy to 12 weeks
new bacterium, with or without the presence of of therapy would be shown if the upper bound-
the initial causative bacteria; and probable fail- ary of the 95% confidence interval for the abso-
ure, defined as the absence of bacteriologic docu- lute between-group difference (the value in the
mentation and the presence of certain macro- 6-week group minus the value in the 12-week
scopic clinical signs of infection (e.g., fistula) group) in the percentage of patients with persis-
and possibly histologic signs (e.g., presence of tent infection within 2 years was not greater
neutrophils). Detailed definitions of the catego- than 10 percentage points. We performed two

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 The n e w e ng l a n d j o u r na l
sensitivity analyses of the primary outcome. In
one, we adjusted the main analysis for stratifica-
tion variables (initial surgical procedure, infect-
ed joint, and episode of infection), and in the
other, data from the patients who were lost to
follow-up or died were removed. Additional de-
tails are provided in the Statistical Analyses sec-
tion in the Supplementary Appendix.
We performed a per-protocol analysis that
excluded patients who were lost to follow-up,
died, were enrolled in the trial but did not meet
one eligibility criterion, received prolonged anti-
biotic therapy for an indication other than the
prosthetic joint infection (which would interfere
with the assessment of the primary outcome), or
did not complete the assigned course of antibi-
otic therapy at the scheduled time (±6 days). We
also performed a post hoc analysis in which only
persistent infections that were diagnosed after
6 weeks of antibiotic therapy were counted, be-
cause the treatment received by the patients dif-
fered only after week 6. In the analyses of the
binary outcomes, the results are presented as the
point estimate for the between-group differenc-
es in the percentage of patients with treatment
failure, and the two-sided 95% confidence inter-
val of the difference was calculated with the use
of the Wilson score method without continuity
correction.12
In all primary outcome analyses, we estimated
the differences in risk in unadjusted models and
models adjusted for stratification factors. Post
hoc analyses were performed with a linear model
with robust standard errors to assess the consis-
tency of the between-group differences in sub-
groups defined according to the stratification
variables. In the analyses of safety outcomes, the
results are presented as the number and percent-
age of patients with an adverse event according
to trial group. Confidence intervals for second-
ary outcomes and subgroup analyses were not
adjusted for multiple comparisons. All analyses
were performed with the use of SAS software,
version 9.4 (SAS Institute), and R version 4.0.2.
R e sult s
Patients
Between November 29, 2011, and January 22,
2015, a total of 410 patients underwent random-
ization across 28 trial sites in France, including
14 university hospital sites (median number of
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of m e dic i n e
patients per trial site, 7; interquartile range, 3 to
19) — 205 patients were assigned to the 6-week
group and 205 to the 12-week group. Consent
was withdrawn after randomization by 2 patients
in the 6-week group and by 4 patients in the 12-
week group, and these patients were not included
in the analyses. Therefore, the trial involved 404
patients (203 in the 6-week group and 201 in the
12-week group) (Fig. 1). Baseline characteristics
were balanced between the two trial groups
(Table 1). The initial surgical management of
prosthetic joint infection among the 404 pa-
tients was débridement with implant retention
in 167 (41.3% [82 patients in the 6-week group
and 85 in the 12-week group]), one-stage im-
plant exchange in 150 (37.1% [77 patients in the
6-week group and 73 in the 12-week group]),
and two-stage implant exchange in 87 (21.5%
[44 patients in the 6-week group and 43 in the
12-week group]). Some between-group differ-
ences were noted with respect to the infecting
pathogen at baseline; Staphylococcus aureus was
identified in 38.0% of the patients in the 6-week
group and in 30.0% of those in the 12-week
group, and coagulase-negative staphylococcus was
noted in 29.5% and 35.2%, respectively (Table 1).
Antibiotic Therapy and Adherence
The antibiotic treatments received by the patients
are listed in Table 1, with additional details pro-
vided in Tables S1 through S3 in the Supplemen-
tary Appendix. Among the 380 patients who re-
ceived at least one oral antibiotic agent, the most
frequently used agents were rifampin (267 pa-
tients [70.3%]) and fluoroquinolone (260 [68.4%]);
a total of 194 patients (51.1%) received both.
Parenteral methicillin or cephalosporin was used
during the initial intravenous phase of treatment
in 136 of the 221 patients with prosthetic joint
infection due to methicillin-susceptible staphy-
lococci. The distribution of antibiotic agents was
similar in both groups.
The median duration of intravenous adminis-
tration was similar in the two groups (9 days;
interquartile range, 5 to 15). The median total
duration of antibiotic therapy was 42 days (inter-
quartile range, 42 to 43) in the 6-week group
and 84 days (interquartile range, 84 to 84) in the
12-week group. Overall, 16 of 192 patients
(8.3%) in the 6-week group and 28 of 194
(14.4%) in the 12-week group reported an omis-
sion of at least one antibiotic dose.
nejm.org May 27, 2021
 Antibiotic Ther apy for Prosthetic Joint Infection

410 Patients were enrolled and underwent

randomization

205 Were assigned to receive 205 Were assigned to receive

6 wk of antibiotic therapy 12 wk of antibiotic therapy

15 Were excluded 17 Were excluded

2 Withdrew consent 4 Withdrew consent
10 Died 10 Died
3 Were lost to follow-up 3 Were lost to follow-up

190 Completed 2-yr follow-up 188 Completed 2-yr follow-up

28 Had major protocol violation

25 Had major protocol violation 22 Had a reduction or extension
22 Had a reduction or extension of antibiotic therapy of
of antibiotic therapy of >6 days
>6 days 3 Received long-term antibiotic
1 Had undergone suboptimal therapy for another indication
initial surgery 2 Had undergone suboptimal
2 Had no microbiologic identi- initial surgery
fication 1 Had infection due to actino-
myces

165 Were included in the 160 Were included in the

per-protocol analysis per-protocol analysis

Figure 1. Enrollment, Randomization, and Follow-up.

A total of 79 patients were excluded from the per-protocol analysis — 26 were missing data on the primary outcome
(20 had died and 6 had been lost to follow-up), and 53 had a major protocol violation.

Primary Outcome Details on the microorganisms that caused per-

In the main modified intention-to-treat analysis,
20 patients who died during follow-up (all from
causes that were considered by the adjudication
committee members to be unrelated to prosthetic
joint infection) were excluded, and missing out-
comes for 6 patients who were lost to follow-up
were considered to be persistent infection. Per-
sistent infection occurred in 35 of 193 patients
(18.1%) in the 6-week group and in 18 of 191
patients (9.4%) in the 12-week group (Table 2).
The difference in the risk of persistent infection
(6-week group vs. 12-week group) was 8.7 per-
centage points (95% confidence interval [CI], 1.8
to 15.6), which did not meet the criterion for
noninferiority. The results were similar after
adjustment for stratification variables (differ-
ence, 9.0 percentage points; 95% CI, 2.3 to 15.7).
The results of the other modified intention-to-
treat and per-protocol analyses were consistent
with the results of the main analysis (Table 2).
sistent infections are provided in Table S4.
The results of the post hoc subgroup analyses
consistently favored the 12-week group, and we
did not find any inconsistency across the sub-
groups (Fig. 2). The results of the post hoc
analysis of persistent infection according to the
infected joint are provided in Tables S5 and S6.
Secondary Outcomes
Treatment failure due to a new infection (new
bacteria with or without the initial bacteria) oc-
curred in 13 of 190 patients (6.8%) in the 6-week
group and in 20 of 188 patients (10.6%) in the
12-week group (difference, −3.8 percentage points;
95% CI, −9.7 to 2.0). Details on the microorgan-
isms that caused new infections are provided in
Table S7. Probable treatment failure occurred
in 8 of 192 patients (4.2%) in the 6-week group
and in 7 of 190 patients (3.7%) in the 12-week
group (difference, 0.5 percentage points; 95%

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Demographic and Clinical Characteristics of the Patients at Baseline and Antibiotic Treatments during the Trial.*

6-Wk Therapy 12-Wk Therapy

Characteristic (N = 203) (N = 201)
Age — yr† 68.4±11.7 69.5±10.7
Male sex — no./total no. (%) 143/203 (70.4) 130/201 (64.7)
History of prosthetic joint infection — no./total no. (%)‡ 30/203 (14.8) 29/201 (14.4)
Baseline surgical procedure — no./total no. (%)
Débridement with implant retention 82/203 (40.4) 85/201 (42.3)
One-stage prosthetic joint implant exchange 77/203 (37.9) 73/201 (36.3)
Two-stage prosthetic joint implant exchange 44/203 (21.7) 43/201 (21.4)
Affected joint — no./total no. (%)
Hip 129/203 (63.5) 126/201 (62.7)
Knee 74/203 (36.5) 75/201 (37.3)
BMI§ 29.9±5.8 29.9±6.2
Coexisting medical condition — no./total no. (%)
Obesity§ 91/192 (47.4) 78/186 (41.9)
ASA score ≥3¶ 51/178 (28.7) 60/179 (33.5)
Clinical presentation — no./total no. (%)
Infection after surgery 68/203 (33.5) 66/201 (32.8)
Acute blood-borne infection 46/203 (22.7) 37/201 (18.4)
Fever 83/196 (42.3) 62/196 (31.6)
Fistula 81/201 (40.3) 76/192 (39.6)
Median time between symptom onset and surgical procedure (IQR) 17 (5–85) 18 (5–110)
— days‖
CRP level at diagnosis of infection — mg/liter** 108.4±99.0 113.2±100.8
Positive blood culture — no./total no. (%) 29/203 (14.3) 23/201 (11.4)
Mono-microorganism — no./total no. (%) 166/203 (81.8) 170/201 (84.6)
Multidrug resistance — no./total no. (%)†† 17/196 (8.7) 19/192 (9.9)
Pathogens identified — no./total no. (%)‡‡
Staphylococcus aureus 90/237 (38.0) 70/233 (30.0)
Coagulase-negative staphylococcus 70/237 (29.5) 82/233 (35.2)
Streptococcus species 32/237 (13.5) 26/233 (11.2)
Gram-negative organisms 21/237 (8.9) 26/233 (11.2)
Other pathogens§§ 24/237 (10.1) 29/233 (12.4)
Antibiotic treatment
Median duration of intravenous administration (IQR) — days¶¶ 9 (5–15) 9 (5–15)
≥1 Oral antibiotic agent — no./total no. (%)‖‖ 191/203 (94.1) 189/201 (94.0)
Rifampin 144/191 (75.4) 123/189 (65.1)
Quinolone 137/191 (71.7) 123/189 (65.1)
Clindamycin 35/191 (18.3) 52/189 (27.5)
Trimethoprim–sulfamethoxazole 22/191 (11.5) 34/189 (18.0)
Amoxicillin with or without clavulanic acid 19/191 (9.9) 21/189 (11.1)

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 Antibiotic Ther apy for Prosthetic Joint Infection

Table 1. (Continued.)

* Plus–minus values are means ±SD. Stratification variables at randomization included history of prosthetic joint infec-
tion, baseline surgical procedure, and affected joint. IQR denotes interquartile range.
† Data on age were available for 203 patients in the 6-week group and 201 patients in the 12-week group.
‡ History of prosthetic joint infection was defined as having had at least one previous episode.
§ Body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. Obesity was defined by a
BMI greater than 30. Data on BMI were available for 192 patients in the 6-week group and 186 patients in the 12-week group.
¶ An American Society of Anesthesiologists (ASA) score of 1 denotes a normal healthy patient, 2 a patient with mild
systemic disease, 3 a patient with severe systemic disease, 4 a patient with severe systemic disease that is a constant
threat to life, 5 a patient in a moribund state, and 6 a patient declared brain-dead.
‖ Data on the time between symptom onset and surgical procedure were available for 198 patients in the 6-week group
and 188 patients in the 12-week group. Among the patients who underwent débridement with implant retention, the
median time between the onset of symptoms and surgical procedure was 5 days (IQR, 3 to 10) among 82 patients in
the 6-week group and 5 days (IQR, 3 to 11) among 83 patients in the 12-week group.
** Data on C-reactive protein (CRP) level were available for 164 patients in the 6-week group and 147 patients in the 12-
week group.
†† Multidrug resistance was defined as an isolate that is not susceptible to at least one agent in at least three antimicro-
bial classes.
‡‡ A total of 68 patients had a polymicrobial infection (37 in the 6-week group and 31 in the 12-week group), so patients
may have had more than one pathogen identified at baseline. A total of 237 pathogens were identified in the 6-week
group, and 233 pathogens were identified in the 12-week group.
§§ Other pathogens included anaerobic bacteria, enterococcus, and other gram-positive bacteria.
¶¶ Data on duration of intravenous route of antibiotic treatment were available for 192 patients in the 6-week group and
194 patients in the 12-week group.
‖‖ Patients may have received more than one oral antibiotic agent.

Table 2. Difference in Risk of Persistent Infection within 2 Years after the Completion of Antibiotic Therapy (Primary Outcome) in the Modified
Intention-to-Treat and Per-Protocol Analyses.

Adjusted Risk
Analysis 6-Wk Therapy 12-Wk Therapy Risk Difference Difference*
no. of patients with event/total no. (%) Percentage points (95% CI)
Modified intention-to-treat
Main analysis in which missing outcomes for patients who 35/193 (18.1) 18/191 (9.4) 8.7 (1.8–15.6) 9.0 (2.3–15.7)
were lost to follow-up were considered to be per-
sistent infections and data from patients who died
removed†
Sensitivity analyses in which data from patients who were
lost to follow-up or died were removed†
Analysis in which all persistent infections were counted 32/190 (16.8) 15/188 (8.0) 8.9 (2.2–15.6) 9.1 (2.6–15.5)
Post hoc analysis in which only persistent infections that 29/187 (15.5) 13/186 (7.0) 8.5 (2.1–15.1) 8.8 (2.5–15.0)
were diagnosed after 6 weeks of antibiotic therapy
were counted‡
Per-protocol§
Analysis in which all persistent infections were counted 29/165 (17.6) 11/160 (6.9) 10.7 (3.6–17.9) 10.6 (3.7–17.5)
Post hoc analysis in which only persistent infections that 27/163 (16.6) 11/160 (6.9) 9.7 (2.7–16.8) 9.7 (2.9–16.5)
were diagnosed after 6 weeks of antibiotic therapy
were counted¶

* In a sensitivity analysis, the risk difference was adjusted for the stratification variables at randomization (initial surgical management strategy,
infected joint, and episode of infection).
† In each trial group, 3 patients were lost to follow-up and 10 patients died.
‡ Treatment failure occurred before 6 weeks in 3 patients in the 6-week group and in 2 patients in the 12-week group.
§ The per-protocol analyses included all patients who underwent randomization, except those who were lost to follow-up, died, were enrolled
in the trial but did not meet one eligibility criterion, received prolonged antibiotic therapy for an indication other than the prosthetic joint in-
fection, or did not complete the assigned course of antibiotic therapy at the scheduled time (±6 days). In the 6-week group, 38 patients were
excluded from the per-protocol analysis, including 3 patients with treatment failure. In the 12-week group, 41 patients were excluded from
the per-protocol analysis, including 4 patients with treatment failure.
¶ Treatment failure occurred before 6 weeks in 2 patients in the 6-week group and in no patient in the 12-week group.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Subgroup 6-Wk Therapy 12-Wk Therapy Risk Difference (95% CI)

no. of patients with event/total no. (%) percentage points
All patients 32/190 (16.8) 15/188 (8.0) 8.9 (2.2 to 15.6)
Surgical procedure
Débridement 23/75 (30.7) 11/76 (14.5) 16.2 (2.9 to 29.5)
Two-stage revision 6/40 (15.0) 2/41 (4.9) 10.1 (−3.1 to 23.3)
One-stage revision 3/75 (4.0) 2/71 (2.8) 1.2 (−4.8 to 7.1)
Affected joint
Hip 19/122 (15.6) 9/117 (7.7) 7.9 (−0.2 to 16.0)
Knee 13/68 (19.1) 6/71 (8.5) 10.7 (−0.9 to 22.2)
Episode of prosthetic joint infection
First 27/162 (16.7) 13/160 (8.1) 8.5 (1.4 to 15.7)
At least the second 5/28 (17.9) 2/28 (7.1) 10.7 (−7.0 to 28.4)
−10 −5 0 5 10 15 20

6-Wk Therapy Better 12-Wk Therapy Better

Figure 2. Exploratory Subgroup Analyses of Persistent Infection within 2 Years after the Completion of Antibiotic Therapy (Primary Outcome).

CI, −3.8 to 4.8). The median duration of hospital
stay was 14 days (interquartile range, 8 to 19) in
the 6-week group and 13 days (interquartile
range, 8 to 19) in the 12-week group. Changes
in the Merle d’Aubigné and Postel hip score and
the Knee Society score between baseline (day 0)
and week 104 are reported in Figures S1 and S2.
Safety Outcomes
During follow-up, 220 serious adverse events
were recorded in 149 patients (78 patients in the
6-week group and 71 patients in the 12-week
group). The most common serious adverse events
were events related to the operative site, musculo-
skeletal events not related to the operative site,
cardiovascular events, neurologic events, and seri-
ous reactions to antibiotics (14 events, mainly
allergy or acute kidney disease) (Table 3). During
the 2-year follow-up, 20 patients died (10 each in
the 6-week and 12-week groups). The causes of
death, all of which were considered to be unre-
lated to prosthetic joint infection, are listed in
Table 3.
Nonserious adverse events (mainly gastroin-
testinal disorders and mycosis) were more com-
mon in the 12-week group than in the 6-week
group. At least one nonserious adverse event was
recorded in 216 patients — 96 of 203 patients
(47.3%) in the 6-week group and 120 of 201 pa-
tients (59.7%) in the 12-week group (P = 0.01)
(Table S8). Clostridioides difficile–associated diar-
rhea occurred in 2 of 203 patients (1.0%) in the
6-week group (1 serious and 1 nonserious) and
1 of 201 patients (0.5%) in the 12-week group
(nonserious). Tendinopathy was reported in 4 pa-
tients (2.0%) in the 6-week group and in 5 patients
(2.5%) in the 12-week group (all nonserious).
Discussion
Among patients with microbiologically con-
firmed prosthetic joint infection that had been
previously managed with a standard surgical
procedure, antibiotic therapy for 6 weeks was
not shown to be noninferior to antibiotic ther-
apy for 12 weeks and resulted in unfavorable
outcomes in a higher percentage of patients. We
did not find clinically significant between-group
differences with respect to serious adverse events,
C. difficile infection, duration of hospital stay, or
functional outcomes.
The strengths of our trial included good re-
tention during the 2-year follow-up and good
adherence to the randomly assigned course of
antibiotic therapy. The patients in this trial came
from many distinct types of participating cen-
ters (e.g., university hospitals, private care cen-
ters, and general hospitals), which improves the
generalizability of the findings. Furthermore, the
percentage of cured patients is consistent with
earlier published data.13,14
Our trial has some limitations. First, most of
the treatment failures in the 6-week group oc-
curred among the patients who had undergone

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 Antibiotic Ther apy for Prosthetic Joint Infection

Table 3. Serious Adverse Events According to Trial Group.

Event 6-Wk Therapy 12-Wk Therapy

Patients with ≥1 serious adverse event — no. of patients/total no. (%) 78/203 (38.4) 71/201 (35.3)*
Serious adverse events — no. of events/total no. (%)
Operative site–related event 28/116 (24.1) 24/104 (23.1)
Antibiotic-related event† 8/116 (6.9) 6/104 (5.8)
Episode of Clostridioides difficile–associated diarrhea 1/116 (0.9) 0/104
Intravenous catheter complication 1/116 (0.9) 1/104 (1.0)
Neurologic event 6/116 (5.2) 8/104 (7.7)
Cardiovascular event‡ 16/116 (13.8) 10/104 (9.6)
Respiratory event 3/116 (2.6) 1/104 (1.0)
Gastrointestinal event 1/116 (0.9) 4/104 (3.9)
Renal event 4/116 (3.4) 0/104
Diabetic event 2/116 (1.7) 2/104 (1.9)
Genitourinary event 3/116 (2.6) 5/104 (4.8)
Musculoskeletal event, not related to operative site§ 15/116 (12.9) 24/104 (23.1)
Skin- or soft-tissue–related event, not related to operative site 4/116 (3.4) 2/104 (1.9)
Anemia 4/116 (3.4) 1/104 (1.0)
Frailty-related event¶ 1/116 (0.9) 0/104
Other event 9/116 (7.8) 6/104 (5.8)
Death from any cause‖ 10/116 (8.6) 10/104 (9.6)

* P = 0.52.
† The antibiotic-related events reported here met the definition of a serious adverse event. These events included pru-
ritic rash, anorexia, acute kidney disease, and nausea (nonserious adverse events are reported in the Supplementary
Appendix).
‡ Most cardiovascular events involved ischemic cardiomyopathy, infective endocarditis, and arrhythmic cardiomyopathy.
§ Most musculoskeletal events involved arthritis and back pain.
¶ A frailty-related event was considered to be a fall and readmission as a result of an inability to live at home.
‖ The cause of death was unknown in 7 patients (4 in the 6-week group and 3 in the 12-week group), stroke in 3 patients
in the 12-week group, cancer in 3 patients (2 in the 6-week group and 1 in the 12-week group), cardiogenic shock in 3 pa-
tients in the 6-week group, septic shock in 2 patients in the 12-week group, terminal liver cirrhosis in 1 patient in the
12-week group, and suicide in 1 patient in the 6-week group.

débridement with implant retention, although no
heterogeneity was found in the subgroup analy-
sis. Future studies should be directed at a single
surgical procedure such as débridement with
implant retention or prosthetic joint replacement
but not both in the same trial. Second, this trial
was open-label, but detection bias was mini-
mized by adjudication of treatment failure by an
independent committee whose members were
unaware of the trial-group assignments. Because
the choice of antibiotics was left to the treating
physician, antibiotic treatment was not stan-
dardized, which led to the use of a wide variety
of molecules, with different routes of adminis-
tration. Prosthetic joint infection is typically man-
aged with surgery and a prolonged course of
antibiotics with an intravenous route of admin-
istration (U.S. standard), which has limited evi-
dence of superiority over an oral route of admin-
istration. In our trial, the duration of intravenous
antibiotic therapy was not standardized and was
shorter than the U.S. standard. Nevertheless, a
recent randomized trial showed that oral anti-
biotic therapy was noninferior to intravenous
therapy for bone and joint infection.15 The pa-
tients included in our trial received intravenous
therapy for a median duration of 9 days (similar
in the two groups), and 63.5% of patients re-
ceived at least 7 days of intravenous therapy.
Moreover, 91.0% of the patients received anti­

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 The n e w e ng l a n d j o u r na l of m e dic i n e

biotics with good oral bioavailability, such as
quinolone, rifampin, clindamycin, and trime-
thoprim–sulfamethoxazole, and 51.1% received
the recommended combination of rifampin and
quinolone. The frequency of use of rifampin is
consistent with the proportion of patients with
staphylococcal infections, current guidelines,5,15,16
and the findings from a randomized trial that
showed the superiority of rifampin use in pa-
tients with prosthetic device–related infections.1
We noted no major differences in the distribu-
tion of antibiotics between the two groups, re-
gardless of the microorganism identified. Some
imbalance between the trial groups at baseline
was noted for the causal pathogens S. aureus and
coagulase-negative staphylococcus.
We found that the largest between-group dif-
ference in treatment failure in favor of 12 weeks
of antibiotic therapy over 6 weeks was among
the patients who had undergone débridement
with implant retention, despite the fact that the
surgical procedure involved the exchange of mo-
bile parts, ample irrigation of the joint, and a
short time between the onset of infection and
surgery (median of 5 days in both groups). A
higher proportion of patients had nonserious
adverse events in the 12-week group than in the
6-week group; the difference was mainly due to
gastrointestinal side effects and mycosis. Such
side effects, although unsurprising, can limit
treatment and should be carefully monitored.
This trial showed that a shorter course of
6 weeks of antibiotic therapy did not meet the
criterion for noninferiority to a longer course of
12 weeks in the treatment of prosthetic joint
infection and resulted in unfavorable outcomes
in a higher percentage of patients, most of whom
had undergone débridement with implant reten-
tion. This difference in risk seemed to be less
marked among the patients who had undergone
one-stage or two-stage implant exchange, but
this observation remains to be explored in a
specific randomized trial.
Supported by a grant from Programme Hospitalier de Re-
cherche Clinique, French Ministry of Health (PHRC PO10-06).
Dr. Druon reports receiving royalties from ASTON-SEM. No
other potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.

Appendix
The authors’ full names and academic degrees are as follows: Prof. Louis Bernard, M.D., Ph.D., Cédric Arvieux, M.D., Benoit Brunsch-
weiler, M.D., Ph.D., Sophie Touchais, M.D., Ph.D., Séverine Ansart, M.D., Ph.D., Jean‑Pierre Bru, M.D., Eric Oziol, M.D., Cyril Boeri,
M.D., Ph.D., Guillaume Gras, M.D., Jérôme Druon, M.D., Philippe Rosset, M.D., Ph.D., Eric Senneville, M.D., Ph.D., Houcine Bentayeb,
M.D., Damien Bouhour, M.D., Gwenaël Le Moal, M.D., Jocelyn Michon, M.D., Hugues Aumaître, M.D., Emmanuel Forestier, M.D.,
Jean‑Michel Laffosse, M.D., Ph.D., Thierry Begué, M.D., Ph.D., Catherine Chirouze, M.D., Ph.D., Fréderic‑Antoine Dauchy, M.D., Ed-
ouard Devaud, M.D., Benoît Martha, M.D., Denis Burgot, M.D., David Boutoille, M.D., Ph.D., Eric Stindel, M.D., Ph.D., Aurélien Dinh,
M.D., Pascale Bemer, M.D., Ph.D., Bruno Giraudeau, Ph.D., Bertrand Issartel, M.D., and Agnès Caille, M.D., Ph.D.
The authors’ affiliations are as follows: the Division of Infectious Diseases (L.B., G.G.), Orthopedic Unit (J.D., P.R.), and INSERM
Centre d’Investigation Clinique 1415 (B.G., A.C.), University Hospital, and University of Tours and University of Nantes, INSERM,
SPHERE (Methods in Patient-Centered Outcomes and Health Research) Unité 1246 (B.G., A.C.), Tours, the Division of Infectious Dis-
eases, University Hospital, Rennes (C.A.), the Orthopedic Unit, University Hospital, Amiens (B.B.), the Orthopedic Unit (S.T.), the Divi-
sion of Infectious Diseases (D. Boutoille), and the Department of Bacteriology (P.B.), University Hospital, Nantes, the Division of Infec-
tious Diseases (S.A.) and Orthopedic Unit (E. Stindel), University Hospital, Brest, the Division of Infectious Diseases, Regional Hospital,
Annecy (J.-P.B.), the Division of Infectious Diseases, Regional Hospital, Beziers (E.O., H.A.), the Orthopedic Unit, University Hospital,
Strasbourg (C.B.), the Division of Infectious Diseases, University Hospital, Tourcoing (E. Senneville), the Division of Infectious Dis-
eases, Regional Hospital, Saint Quentin (H.B.), the Division of Infectious Diseases, General Hospital, Bourg en Bresse (D. Bouhour),
the Division of Infectious Diseases, University Hospital, Poitiers (G.L.M.), the Division of Infectious Diseases, University Hospital, Caen
(J.M.), the Division of Infectious Diseases, Regional Hospital, Chambery (E.F.), the Orthopedic Unit, University Hospital, Toulouse
(J.M.L.), the Orthopedic Unit, University Hospital, Clamart (T.B.), the Division of Infectious Diseases, University Hospital, Besançon
(C.C.), the Division of Infectious Diseases, University Hospital, Bordeaux (F.-A.D.), the Division of Internal Medicine, Pointoise Hospi-
tal, Pointoise (E.D.), the Division of Infectious Diseases, Regional Hospital, Chalon (B.M.), the Orthopedic Unit, Blois Polyclinic, La
Chaussée-Saint-Victor (D. Burgot), the Mobile Unit of the Infectious Referents, University Hospital, Garches (A.D.), and the Mobile Unit
of the Infectious Referents, Villeurbanne (B.I.) — all in France.

References
1. Zimmerli W, Widmer AF, Blatter M,
Frei R, Ochsner PE. Role of rifampin for
treatment of orthopedic implant-related
staphylococcal infections: a randomized
controlled trial. JAMA 1998;​279:​1537-41.
2. Chaussade H, Uçkay I, Vuagnat A, et al.
Antibiotic therapy duration for prosthetic
joint infections treated by debridement
and implant retention (DAIR): similar
long-term remission for 6 weeks as com-
pared to 12 weeks. Int J Infect Dis 2017;​
63:​37-42.
3. Bernard L, Hoffmeyer P, Assal M,
Vaudaux P, Schrenzel J, Lew D. Trends in
the treatment of orthopaedic prosthetic

2000 n engl j med 384;21 nejm.org May 27, 2021

The New England Journal of Medicine

Downloaded from nejm.org on May 18, 2024. For personal use only.
No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved.
 Antibiotic Ther apy for Prosthetic Joint Infection

infections. J Antimicrob Chemother 2004;​
53:​127-9.
4. Cobo J, Miguel LGS, Euba G, et al.
Early prosthetic joint infection: outcomes
with debridement and implant retention
followed by antibiotic therapy. Clin Micro-
biol Infect 2011;​17:​1632-7.
5. Osmon DR, Berbari EF, Berendt AR,
et al. Executive summary: diagnosis and
management of prosthetic joint infection:
clinical practice guidelines by the Infec-
tious Diseases Society of America. Clin
Infect Dis 2013;​56:​1-10.
6. Farhad R, Roger P-M, Albert C, et al.
Six weeks antibiotic therapy for all bone
infections: results of a cohort study. Eur J
Clin Microbiol Infect Dis 2010;​29:​217-22.
7. Lora-Tamayo J, Euba G, Cobo J, et al.
Short- versus long-duration levofloxacin
plus rifampicin for acute staphylococcal
prosthetic joint infection managed with
implant retention: a randomised clinical
trial. Int J Antimicrob Agents 2016;​48:​
310-6.
8. Bernard L, Dinh A, Ghout I, et al. Anti-
biotic treatment for 6 weeks versus 12
weeks in patients with pyogenic vertebral
osteomyelitis: an open-label, non-inferi-
ority, randomised, controlled trial. Lancet
2015;​385:​875-82.
9. Société de Pathologie Infectieuse de
Langue Française. Recommendations for
clinical practice: osteo-articular infection
therapy according to materials used (pros-
thesis, implants, osteosynthesis). Med Mal
Infect 2009;​39:​745-74. (In French.)
10. d’Aubigne RM, Postel M. Functional
results of hip arthroplasty with acrylic
prosthesis. J Bone Joint Surg Am 1954;​36-
A:​451-75.
11. Scuderi GR, Bourne RB, Noble PC,
Benjamin JB, Lonner JH, Scott WN. The
new Knee Society knee scoring system.
Clin Orthop Relat Res 2012;​470:​3-19.
12. Newcombe RG. Interval estimation
for the difference between independent
proportions: comparison of eleven meth-
ods. Stat Med 1998;​17:​873-90.
13. Zimmerli W, Trampuz A, Ochsner PE.
Prosthetic-joint infections. N Engl J Med
2004;​351:​1645-54.
14. Löwik CAM, Parvizi J, Jutte PC, et al.
Debridement, antibiotics, and implant re-
tention is a viable treatment option for
early periprosthetic joint infection pre-
senting more than 4 weeks after index ar-
throplasty. Clin Infect Dis 2020;​71:​630-6.
15. Li H-K, Rombach I, Zambellas R, et al.
Oral versus intravenous antibiotics for
bone and joint infection. N Engl J Med
2019;​380:​425-36.
16. Høiby N, Bjarnsholt T, Moser C, et al.
ESCMID guideline for the diagnosis and
treatment of biofilm infections 2014. Clin
Microbiol Infect 2015;​21:​Suppl 1:​S1-S25.
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